1 . Field of the Invention
This invention relates to compounds derived from adenosine and analogues thereof, to pharmaceutical compositions containing such compounds, to their use in treating hypertension and myocardial ischemia, to their use as cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, and to their use as antilipolytic agents which reduce plasma lipid levels, serum triglyceride levels, and plasma cholesterol levels. and to methods and intermediates used in the preparation of such compounds.
Hypertension
Hypertension, a condition of elevated blood pressure, affects a substantial number of the human population. Consequences of persistent hypertension include vascular damage to the ocular, renal, cardiac and cerebral systems, and the risk of these complications increases as blood pressure increases. Basic factors controlling blood pressure are cardiac output and peripheral vascular resistance, with the latter being the predominant common mechanism which is controlled by various influences. The sympathetic nervous system regulates peripheral vascular resistance through direct effects on alpha- and beta-adrenergic receptors as well as through indirect effects on renin release. Drug therapy is aimed at specific components of these blood pressure regulatory systems, with different mechanisms of action defining the several drug classes including diuretics, beta-adrenergic receptor antagonists (beta-blockers), angiotensin-converting enzyme (ACE) inhibitors, and calcium channel antagonists.
Thiazide-type diuretics are used in hypertension to reduce peripheral vascular resistance through their effects on sodium and water excretion. This class of drugs includes hydrochlorothiazide, chlorothiazide, methyclothiazide, and cyclothiazide, as well as related agents indapamide, metolazone, and chlorthalidone. Although the beta-blocker mechanism of action was once believed to be blockade of the beta1-adrenergic receptor subtype in the heart to reduce heart rate and cardiac output, more recent beta-blockers with intrinsic sympathomimetic activity (ISA), including pindolol, acebutolol, penbutolol, and carteolol, are as effective as non-ISA beta-blockers, causing less reduction in heart rate and cardiac output. Other postulated mechanisms for these drugs include inhibition of renin release, a central effect, and an effect at pre-synaptic beta-adrenergic receptors resulting in inhibition of norepinephrine release. Cardioselective beta-blockers metoprolol (Lopressor-Geigy), acebutolol (Sectral-Wyeth), and atenolol (Tenormin-ICI), at low doses, have a greater effect on beta1-adrenergic receptors than on beta2-adrenergic receptor subtypes located in the bronchi and blood vessels. Nonselective beta-blockers act on both beta-adrenergic receptor subtypes and include propranolol (Inderal-Ayerst), timolol (Blocadren-Merck), nadolol (Corgard-Squibb), pindolol (Visken-Sandoz), penbutolol (Levatol-Hoechst-Roussel), and carteolol (Cartrol-Abbott). Adverse effects of beta-blockers include asymptomatic bradycardia, exacerbation of congestive heart failure, gastrointestinal disturbances, increased airway resistance, masked symptoms of hypoglycemia, and depression. They may cause elevation of serum triglycerides and may lower high-density lipoprotein cholesterol.
ACE inhibitors prevent the formation of angiotensin II and inhibit breakdown of bradykinin. Angiotensin II is a potent vasoconstrictor and also stimulates the secretion of aldosterone. By producing blockade of the renin-angiotensin-aldosterone system, these agents decrease peripheral vascular resistance, as well as sodium and water retention. In addition, ACE inhibitors increase levels of bradykinin and prostaglanidins, endogenous vasodilators. Captopril (Capoten-Squibb) and Enalapril (Vasotec-Merck) are the leading ACE inhibitors. Adverse effects of the ACE inhibitors include rash, taste disturbance, proteinuria, and neutropenia.
The calcium channel antagonists reduce the influx of calcium into vascular smooth muscle cells and produce systemic vasodilation, resulting in their antihypertensive effect. Other effects of calcium channel antagonists include interference with action of angiotensin II and alpha2-adrenergic receptor blockade, which may add to their antihypertensive effects. Calcium channel antagonists do not have the adverse metabolic and pharmacologic effects of thiazides or beta-blockers and may therefore be useful in patients with diabetes, peripheral vascular disease, or chronic obstructive pulmonary disease. Two calcium channel antagonists, Verapamil and diltiazem, have serious adverse cardiovascular effects on atrioventricular cardiac conduction in patients with preexisting conduction abnormalities, and they may worsen bradycardia, heart block, and congestive heart failure. Other minor adverse effects of calcium channel antagonists include peripheral edema, dizziness, light-headedness, headache, nausea, and flushing, especially with nifedipine and nicardipine.
Many other agents are available to treat essential hypertension. These agents include prazosin and terazocin, alpha1-adrenergic receptor antagonists whose antihypertensive effects are due to resultant arterial vasodilation; clonidine, an alpha2-adrenergic agonist which acts centrally as well as peripherally at inhibitory alpha2-adretiergic receptors, decreasing sympathetic response. Other centrally acting agents include methyldopa, guanabenz, and guanfacine; reserpine, which acts by depleting stores of catecholamines; guanadrel, a peripheral adrenergic antagonist similar to guanethidine with a shorter duration of action; and direct-acting vasodilators such as hydralazine and minoxidil. These agents, although effective, produce noticeable symptomatic side effects, including reflex sympathetic stimulation and fluid retentions orthostatic hypotension, and impotence.
Many antihypertensive agents activate compensatory pressor mechanisms, such as increased renin release, elevated aldosterone secretion and increased sympathetic vasoconstrictor tone, which are designed to return arterial pressure to pretreatment levels, and which can lead to salt and water retention, edema and ultimately to tolerance to the antihypertensive actions of the agent. Furthermore, due to the wide variety of side effects experienced with the present complement of antihypertensive drugs and the problems experienced therewith by special populations of hypertensive patients, including the elderly, blacks, and patients with chronic obstructive pulmonary disease, diabetes, or peripheral vascular diseases, there is a need for additional classes of drugs to treat hypertension.
Ischemia
Myocardial ischemia is the result of an imbalance of myocardial oxygen supply and demand and includes exertional and vasospastic myocardial dysfunction. Exertional ischemia is generally ascribed to the presence of critical atherosclerotic stenosis involving large coronary arteries resulting in a reduction in subendocardial flow. Vasospastic ischemia is associated with a spasm of focal variety, whose onset is not associated with exertion or stress. The spasm is better defined as an abrupt increase in vascular tone. Mechanisms for vasospastic ischemia include: (i) Increased vascular tone at the site of stenosis due to increased catecholamine release: (ii) Transient intraluminal plugging and (iii) Release of vasoactive substances formed by platelets at the site of endothelial lesions.
The coronary circulation is unique since it perfuses the organ which generates the perfusion pressure for the entire circulation. Thus, interventions which alter the state of the peripheral circulation and contractility will have a profound effect on coronary circulation. The regulatory component of the coronary vasculature is the small coronary arterioles which can greatly alter their internal diameter. The alteration of the internal radius is the result of either intrinsic contraction of vascular smooth muscle (autoregulation) or extravascular compression due to ventricular contraction. The net effect of therapies on the ischemic problem involves a complex interaction of opposing factors which determine the oxygen supply and demand.
Cardioprotection and Prevention of Ischemic Injury
The development of new therapeutic agents capable of limiting the extent of myocardial injury, i.e., the extent of myocardial infarction, following acute myocardial ischemia is a major concern of modern cardiology.
The advent of thrombolytic (clot dissolving) therapy during the last decade demonstrates that early intervention during heart attack can result in significant reduction of damage to myocardial tissue. Large clinical trials have since documented that thrombolytic therapy decreases the risk of developing disturbances in the heartbeat and also maintains the ability of the heart to function as a pump. This preservation of normal heart function has been shown to reduce long-term mortality following infarction.
There has also been interest in the development of therapies capable of providing additional myocardial protection which could be administered in conjunction with thrombolytic therapy, or alone, since retrospective epidemiological studies have shown that mortality during the first few years following infarction appears to be related to original infarct size.
In preclinical studies of infarction, conducted in a variety of animal models, many types of pharmacological agents such as calcium channel blockers, prostacyclin analogues, and agents capable of inhibiting certain metabolic pathways have been shown to be capable of reducing ischemic injury in several animal species.
Recent studies have demonstrated that exposure of the myocardium to brief periods of ischemia (interruption of blood flow to the heart) followed by reperfusion (restoration of blood flow) is able to protect the heart from the subsequent ischemic injury that would otherwise result from subsequent exposure to a longer period of ischemia. This phenomenon has been termed myocardial preconditioning and is believed to be partially attributable to the release of adenosine during the preconditioning period.
Other studies have shown that adenosine and adenosine analogues reduce the extent of tissue damage that is observed following the interruption of blood flow to the heart in a variety of models of ischemic injury in several species (see, for example, Toombs, C. et al., xe2x80x9cMyocardial protective effects of adenosine. Infarct size reduction with pretreatment and continued receptor stimulation during ischemia.xe2x80x9d, Circulation 86, 986-994 (1992); Thornton, J. et al., xe2x80x9cIntravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction.xe2x80x9d, Circulation 85, 659-665 (1992); and Downey, J. xe2x80x9cIschemic preconditioningxe2x80x94nature""s own cardioprotective intervention.xe2x80x9d, Trends Cardiovasc. Med. 2(5), 170-176 (1992)).
Compounds of the present invention mimic myocardial preconditioning, thereby ameliorating ischemic injury or producing a reduction in the size of myocardial infarct consequent to myocardial ischemia and are thereby useful as cardioprotective agents.
Antilipolysis
Hyperlipidemia and hypercholesterolemia are known to be two of the prime risk factors for atherosclerosis and coronary heart disease, the leading cause of death and disability in Western countries. Although the etiology of atherosclerosis is multifactorial, the development of atherosclerosis and conditions including coronary artery disease, peripheral vascular disease and cerbrovascular disease resulting from restricted blood flow, are associated with abnormalities in serum cholesterol and lipid levels. The etiology of hypercholesterolemia and hyperlipidemia is primarily genetic, although factors such as dietary intake of saturated fats and cholesterol may contribute.
The antilipolytic activity of adenosine and adenosine analogues arises from the activation of the A1 receptor subtype (Lohse, M. J., et al., Recent Advances in Receptor Chemistry, Melchiorre, C. and Gianella, Eds, Elsevier Science Publishers B.V., Amsterdam, 1988, 107-121). Stimulation of this receptor subtype lowers the intracellular cyclic AMP concentration in adipocytes. Cyclic AMP is a necessary co-factor for tile enzyme lipoprotein lipase which hydrolytically cleaves triglycerides to free fatty acids and glycerol in adipocytes (Egan, J. J., et al., Proc. Natl. Acad. Sci. 1992 (89), 8357-8541). Accordingly, reduction of intracellular cyclic AMP concentration in adipocytes reduces lipoprotein lipase activity and, therefore, the hydrolysis of triglycerides.
Elevated blood pressure and plasma lipids, including triglycerides, are two well accepted risk factors associated with mortality resulting from cardiovascular disease.
For the diabetic patient, where the likelihood of mortality from cardiovascular disease is substantially greater, the risk associated with these factors is further magnified (Bierman, E. L., Arteriosclerosis and Thrombois 1992 (12), 647-656). Additionally, data suggest that excessive lipolysis is characteristic of non-insulin dependent diabetes and possibly contributes to insulin resistance and hyperglycemia (Swislocki, A. L., Horm. Metab. Res. 1993 (25), 90-95).
Compounds of the present invention, as antihypertensive and antilipolytic agents, are useful in the treatment and amelioration of both vascular and metabolic risk factors, and are of particular value and utility.
The present invention relates to a class of adenosine analogues and their utility in the treatment of hypertension, myocardial ischemia, as cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, and as antilipolytic agents which reduce plasma lipid levels, serum triglyceride levels, and plasma cholesterol levels, and to methods and intermediates used in the preparation of such compounds.
2. Reported Developments
Adenosine has a wide variety of physiological and pharmacological actions including a marked alteration of cardiovascular and renal function. In animals and man, intravenous injection of the adenosine nucleotide causes hypotension.
The physiological and pharmacological actions of adenosine are mediated through specific receptors located on cell surfaces. Four adenosine receptor subtypes, designated as A1, A2A, A2B, and A3 receptors, have been identified. The AI receptor inhibits the formation of cAMP by suppressing the activity of adenylate cyclase, while stimulation of A2 receptors increases adenylate cyclase activity and intracellular cAMP. Each receptor appears to mediate specific actions of adenosine in different tissues: for example, the vascular actions of adenosine appears to be mediated through stimulation of A2 receptors, which is supported by the positive correlation between cAMP generation and vasorelaxation in adenosine-treated isolated vascular smooth muscle; while stimulation of the cardiac A1 receptors reduces cAMP generation in the heart which contributes to negative drorpotropic, inotropic and chronotropic cardiac effects. Consequently, unlike most vasodilators, adenosine administration does not produce a reflex tachycardia.
Adenosine also exerts a marked influence on renal function. Intrarenal infusion of adenosine causes a transient fall in renal blood flow and an increase in renal vascular resistance. With continued infusion of adenosine, renal blood flow returns to control levels and renal vascular resistance is reduced. The initial renal vasoconstrictor responses to adenosine are not due to direct vasoconstrictor actions of the nucleotide, but involve an interaction between adenosine and the renin-angiotensin system.
Adenosine is widely regarded as the primary physiological mediator of reactive hyperemia and autoregulation of the coronary bed in response to myocardial ischemia. It has been reported that the coronary endothelium possesses adenosine A2 receptors linked to adenylate cyclase, which are activated in parallel with increases in coronary flow and that cardiomyocyte receptors are predominantly of the adenosine A1 subtype and associated with bradycardia. Accordingly, adenosine offers a unique mechanism of ischemic therapy.
Cardiovascular responses to adenosine are short-lived due to the rapid uptake and metabolism of the endogenous nucleotide. In contrast, the adenosine analogues are more resistant to metabolic degradation and are reported to elicit sustained alterations in arterial pressure and heart rate.
Several potent metabolically-stable analogues of adenosine have been synthesized which demonstrate varying degrees of selectivity for the two receptor subtypes. Adenosine agonists have generally shown greater selectivity for A1 receptors as compared to A2 receptors. Cyclopentyladenosine (CPA) and R-phenylisopropyl-adenosine (R-PIA) are standard adenosine agonists which show marked selectivity for the A1 receptor (A2/A1 ratio=780 and 106, respectively). In contrast, N-5xe2x80x2-ethyl-carboxamido adenosine (NECA) is a potent A2 receptor agonist (Ki-12 nM) but has equal affinity for the A1 receptor (Ki-6.3 nM; A2/A1 ratio=1.87). Until recently, CV-1808 was the most selective A2 agonist available (A2/A1=0.19), even though the compound was 10-fold less potent than NECA in its affinity for the A2 receptor. In recent developments, newer compounds have been disclosed which are very potent and selective A2 agonists (Ki=3-8 nM for A1; A2/A1ratio=0.027-0.042) (C. E. Mxc3xcller and T. Scior, Pharmaceutica Acta Hevetiae 68 (1993) 77-111).
Various N6-aryl and N6-heteroarylalkyl substituted adenosines, and substituted-(2-amino and 2-hydroxy)adenosines, have been reported in the literature as possessing varied pharmacological activity, including cardiac and circulatory activity. See, for example, British Patent Specification 1,123,245, German Offen. 2,136,624, German Off 2,059.922, German Offen. 2,514,284, South African Patent No. 67/7630, U.S. Pat. No. 4,501,735, EP Publication No. 0139358 (disclosing N6-[geminal diaryl substiuted alkyl]adenosines), EP Patent Application Ser. No. 88106818.3 (disclosing that N6-heterocyclic-substituted adenosine derivatives exhibit cardiac vasodilatory activity), German Offen. 2,131,938 (disclosing aryl and heteroaryl alkyl hydrazinyl adenosine derivatives), German Offen. 2,151,013 (disclosing N6-aryl and heteroaryl substituted adenosines), German Offen. 2,205,002 (disclosing adenosines with N6-substituents comprising bridged ring structures linking the N6-nitrogen to substituents including thienyl) and South African Patent No. 68/5477 (disclosing N6-indolyl substituted-2-hydroxy adenosines).
U.S. Pat. No. 4,954,504 and EP Publication No. 0267878 disclose generically that carbocyclic ribose analogueues of adenosine, and pharmaceutically acceptable esters thereof, substituted in the 2-and/or N6-positions by aryl lower alkyl groups including thienyl, tetrahydropyranyl, tetrahydrothiopyranyl, and bicyclic benzo fused 5- or 6-membered saturated heterocyclic lower alkyl derivatives exhibit adenosine receptor agonist properties. Adenosine analogueues having thienyl-type substituents are described in EP Publication No. 0277917 (disclosing N6-substituted-2-heteroarylalkylamino substituted adenosines including 2-[(2-[thien-2-yl]ethyl)amino] substituted adenosine), German Offen. 2,139,107 (disclosing N6-[benzothienylmethyl]-adenosine), PCT WO 85/04882 (disclosing that N6-heterocyclicalkyl-substituted adenosine derivatives, including N6-[2-(2-thienyl)ethyl]amino-9-(D-ribofuranosyl)-9H-purine, exhibit cardiovascular vasodilatory activity and that N6-chiral substituents exhibit enhanced activity), EP Published Application No. 0232813 (disclosing that N6-(1-substituted thienyl)cyclopropylmethyl substituted adenosines exhibit cardiovascular activity), U.S. Pat. No. 4,683,223 (disclosing that N6-benzothiopyranyl substituted adenosines exhibit antihypertensive properties), PCT WO 88/03147 and WO 88/03148 (disclosing that N6-[2-aryl-2-(thien-2-yl)ethyl substituted adensosines exhibit antihypertensive properties), U.S. Pat. Nos. 4,636,493 and 4,600,707 (disclosing that N6-benzothienylethyl substituted adenosines exhibit antihypertensive properties).
Adenosine-5xe2x80x2-carboxylic acid amides are disclosed as having utility as anti-hypertensive and anti-anginal agents in U.S. Pat. No. 3,914,415, while U.S. Pat. No. 4,738,954 discloses that N6-substituted aryl and arylalkyl-adenosine 5xe2x80x2-ethyl carboxamides exhibit various cardiac and antihypertensive properties.
N6-alkyl-2xe2x80x2-O-alkyl adenosines are disclosed in EP Publication No. 0,378,518 and UK Patent Application No. 2,226,027 as having antihypertensive activity. N6-alkyl-2xe2x80x2,3xe2x80x2-di-O-alkyl adenosines are also reported to have utility as antihypertensive agents, U.S. Pat. No. 4,843,066.
Adenosine-5xe2x80x2-(N-substituted)carboxamides and carboxylate esters and N1-oxides thereof are reported to be coronary vasodilators, Stein, et al., J. Med. Chem. 1980, 23, 313-319 and J. Med. Chem. 19 (10), 1180 (1976). Adenosine-5xe2x80x2-carboxamides and N1-oxides thereof are also reported as small animal poisons in U.S. Pat. No. 4,167,565.
The antilipolytic activity of adenosine is described by Dole, V. P., J. Biol. Chem. 236 (12), 3125-3130 (1961). Inhibition of lipolysis by (R)-N6 phenylisopropyl adenosine is disclosed by Westermann, E., et al., Adipose Tissue, Regulation and Metabolic Functions, Jeanrenaud, B. and Hepp, D. Eds., George Thieme, Stuttgart, 47-54 (1970). N6-mono- and disubstituted adenosine analogueues are disclosed as having antilipolytic, antihypercholesterolemic, and antilhyperlipemic activity in U.S. Pat. Nos. 3,787,391; 3,817,981; 3,838,147; 3,840,521; 3,835,035; 3,851,056; 3,880,829; 3,929,763; 3,929,764; 3,988,317; and 5,032,583.
N6-substituted adenosines and analogues, useful in treating gastroinstestinal motility disorders, have been reported in EP Published Applications Nos. 0423776, and 0423777.
N6-heterocyclyl compounds derived from adenosine and analogues thereof, and their use in treating hypertension and myocardial ischemia, their use as cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, their use as antilipolytic agents which reduce plasma lipid levels, serum triglyceride levels, and plasma cholesterol levels, are disclosed in U.S. patent application Ser. No. 08/316,761, filed Oct. 3, 1994, assigned to the same assignee as the present application, and for which a Notice of Allowance was mailed Mar. 26, 1996. N6-heterocyclyl compounds derived from adenosine and analogues thereof, and their use in treating myocardial ischemia and hypertension, are also disclosed in U.S. Pat. No. 5,364,862, filed Oct. 2, 1992, and which is assigned to the same assignee as the present application.
It is believed that the reported toxicity, CNS properties and heart rate elevation associated with adenosine analogueues have contributed to the difficulties preventing the development of a commercial adenosine analogue antihypertensive/antiischemic agent. The present invention relates to a class of metabolically stable adenosine analogues, and derivatives thereof, possessing unexpectedly desirable pharmacological properties, i.e. are anti-hypertensive, cardioprotective, anti-ischemic, and antilipolytic agents having a unique therapeutic profile.
The compounds of the present invention are described by Formula I 
wherein:
K is N, Nxe2x86x92O, or CH;
Q is CH2 or O;
R6 is hydrogen, alkyl, allyl, 2-methylallyl, 2-butenyl, or cycloalkyl; 
where the nitrogen of the ring of X is substituted by Y;
E is O or S;
Y is hydrogen, alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl
n and p are independently 0, 1, 2, or 3, provided that n+p is at least 1; 
T is hydrogen, alkyl, acyl, thioacyl, halo, carboxyl, or R3Oxe2x80x94CH2;
R1, R2, and R3 are independently H, alkyl, or cycloalkyl;
A is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or ORxe2x80x2;
B is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or ORxe2x80x3;
Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, or, when A and B are ORxe2x80x2 and ORxe2x80x3, respectively, Rxe2x80x2 and Rxe2x80x3 together may form 
where Rc is hydrogen or alkyl, 
where Rd and Re are independently hydrogen, alkyl, or together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group;
or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable prodrug thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.
This invention relates also to methods for treating cardiovascular disease marked by hypertension or myocardial ischemia using pharmaceutical compositions including an anti-hypertensive effective amount or an anti-ischemic effective amount of a compound of Formula I above, to a method for ameliorating ischemic injury or myocardial infarct size using pharmaceutical compositions including a cardioprotective amount of a compound of Formula I above, to a method for treating hyperlipidemia or hypercholesterolemia using pharmaceutical compositions including an antilipolytic amount of Formula I, and to methods and intermediates used in the preparation of such compounds.
As used above and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cAcylxe2x80x9d means a straight or branched alkyl-Cxe2x95x90O group. xe2x80x9cThioacylxe2x80x9d means a straight or branched alkyl-Cxe2x95x90S group. Preferred acyl and thioacyl groups are lower alkanoyl and lower thioalkanoyl having from 1 to about 6 carbon atoms in the alkyl group.
xe2x80x9cAlkylxe2x80x9d means a saturated aliphatic hydrocarbon group which may be straight or branched and having about 1 to about 20 carbon atoms in the chain. Preferred alky groups may be straight or branched and have about 1 to about 10 carbon atoms in the chain. Branched means that a lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain.
xe2x80x9cLower alkylxe2x80x9d means an alkyl group having 1 to about 6 carbons.
xe2x80x9cCycloalkylxe2x80x9d means an aliphatic ring having 3 to about 10 carbon atoms in the ring. Preferred cycloalkyl groups have 4 to about 7 carbon atoms in the ring.
xe2x80x9cCarbamoylxe2x80x9d means an 
group. Alkylcarbamoyl and dialkylcarbamoyl means that the nitrogen of the carbamoyl is substituted by one or two alkyl groups, respectively.
xe2x80x9cCarboxylxe2x80x9d means a COOH group.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-O group in which xe2x80x9calkylxe2x80x9d is as previously described. Lower alkoxy groups are preferred. Exemplary groups include methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.
xe2x80x9cAlkoxyalkylxe2x80x9d means an alkyl group, as previously described, substituted by an alkoxy group, as previously described.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkoxy-Cxe2x95x90O group.
xe2x80x9cAralkylxe2x80x9d means an alkyl group substituted by an aryl radical, wherein xe2x80x9carylxe2x80x9d means a phenyl or naphthyl. xe2x80x9cSubstituted aralkylxe2x80x9d and xe2x80x9csubstituted arylxe2x80x9d means that the aryl group, or the aryl group of the aralkyl group is substituted with one or more substituents which include alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkyl amino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, trihaloalkyl, carboxyalkyl or carbamoyl.
xe2x80x9cAralkoxycarbonylxe2x80x9d means an aralkyl-Oxe2x80x94Cxe2x95x90O group.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94Cxe2x95x90O group.
xe2x80x9cCarbalkoxyxe2x80x9d means a carboxyl substituent esterified with an alcohol of the formula CnH2n+1OH, wherein n is from 1 to about 6.
xe2x80x9cHalogenxe2x80x9d (or xe2x80x9chaloxe2x80x9d) means chlorine (chloro), fluorine (fluoro), bromine (bromo) or iodine (iodo).
xe2x80x9cHeterocyclylxe2x80x9d means about a 4 to about a 10 membered ring structure in which one or more of the atoms in the ring is an element other than carbon, e.g., N, O or S. Heterocyclyl may be aromatic or non-aromatic, i.e., may be saturated, partially or fully unsaturated.
Preferred heterocyclyl groups include pyridyl, pyridazinyl, pyrimidinyl, isoquinolinyl, quinolinyl, quinazolinyl, imidazolyl, pyrrolyl, furanyl, thienyl, thiazolyl, benzothiazolyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and morphonlinyl groups.
xe2x80x9cSubstituted heterocyclylxe2x80x9d means that the heterocyclyl group is substituted by one or more substituents wherein the substituents include alkoxy, alkylamino, aryl, carbalkoxy, carbamoyl, cyano, halo, heterocyclyl, trihalomethyl, hydroxy, mercaptyl, alkylmercaptyl or nitro.
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl group substituted by a hydroxy group. Hydroxy lower alkyl groups are preferred. Exemplary preferred groups include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl.
xe2x80x9cProdrugxe2x80x9d means a compound which is rapidly transformed in vivo to yield the parent peptide compound, for example by hydrolysis in blood. xe2x80x9cPharmaceutically acceptable prodrugxe2x80x9d means a compound which is, within the scope of sound medical judgement, suitable for pharmaceutical use in a patient without undue toxicity, irritation, allergic response, and the like, and effective for the intended use, including a pharmaceutically acceptable ester as well as a zwitterionic form, where possible, of the peptide compounds of the invention. Pharmaceutically acceptable prodrugs according to the invention are described in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
xe2x80x9cSolvatexe2x80x9d means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. xe2x80x9cSolvatexe2x80x9d encompasses both solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates, and the like. xe2x80x9cHydratexe2x80x9d is a solvate wherein the solvent molecule(s) is/are H2O.
xe2x80x9cCardioprotectionxe2x80x9d refers to the effect whereby the myocardium is made less susceptible to ischemic injury and myocardial infarct consequent to myocardial ischemia.
xe2x80x9cAmelioration of ischemic injuryxe2x80x9d means the prevention or reduction of ischemic injury to the myocardium consequent to myocardial ischemia.
xe2x80x9cAmelioration of myocardial infarct sizexe2x80x9d means the reduction of the myocardial infarct size, or the prevention of myocardial infarct, consequent to myocardial ischemia.
The compounds of Formula I contain chiral (asymmetric) centers. The invention includes the individual stereoisomers and mixtures thereof. The individual isomers are prepared or isolated by methods well known in the art or by methods described herein.
The compounds of the invention may be used in the form of the free base, in the form of acid addition salts or as hydrates. All such forms are within the scope of the invention. Acid addition salts are simply a more convenient form for use. In practice, use of the salt form inherently amounts to use of the base form. The acids which may be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the recipient in pharmaceutical doses of the salts, so that the beneficial anti-hypertensive, cardioprotective, anti-ischemic, and antilipolytic effects produced by the free base are not vitiated by side effects ascribable to the anions. Although pharamaceutically acceptable salts of the compounds of the invention are preferred, all acid addition salts are useful as sources of the free base form, even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification and identification, or when it is used as an intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, fumaric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid and the like. The corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartarate, methanesulfonate, fumarate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfonate and quinate, respectively.
The acid addition salts of the compounds of the invention are conveniently prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
Included within the scope of Formula I are classes of compounds which may be characterized generally as N6-substituted adenosines; N6-substituted carbocyclic adenosines (or, alternatively, dihydroxy[N6- substituted-9-adenyl]cyclopentanes) and N-oxides thereof; and N6-substituted-Nxe2x80x2-1-deazaaristeromycins (or, alternatively, dihydroxy[N7-substituted[4,5-b]imidazopyridyl]-cyclopentanes). Also within the scope of Formula I are the 5xe2x80x2-alkylcarboxamide derivatives of the adenosines, the carbocyclic adenosines and the 1-deazaaristeromycins, the derivatives of compounds of the above classes in which one or both of the 2- or 3-hydroxyl groups of the cyclopentane ring or, in the cases of classes of compounds containing the ribose moiety, the 2xe2x80x2- or 3xe2x80x2-hydroxyl groups of the ribose ring are substituted. Such derivatives may themselves comprise the biologically active chemical entity useful in the treatment of hypertension and myocardial ischemia, and as cardioprotective and antilipolytic agents, or may act as pro-drugs to such biologically active compounds which are formed therefrom under physiological conditions.
Representative compounds of the invention include: (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(5-chloropyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]- tetrahydrofuran-3,4-diol, (2R,3S,4R,5R)-2-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3(R)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(4-trifuoromethylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R) 2-hydroxymethyl-5-[6- [1-(5-bromopyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-(6-(1-(4-nitrophenyl)-pyrrolidin-3(S)-ylamino)-purin-9-yl) tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-(5xe2x80x2-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]-bipyridinyl-3-yl)-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5- [6-(pheylpyrrolidin-3(S)-ylamino)-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-(1-pyridin-2-ylpyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[I-(4-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(5-methylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5- [6- [1-(5-thiophen-2-ylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(5-methylmercaptopyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(6-methoxypyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R) -2-hydroxymethyl-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(6-chloropyridazin-3-yl)pyrrolidin-3-ylamino]-purin-9-yl]-tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-methoxymethyl-5-[6-[1-(5 trifluoromethylpyridin-2yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (1S,2R,3S ,4R)-2,3-dihydroxy-4-[6-[1-(5-trifluormethylpyridin-2-yl)pyrrolidin-3-ylamino]-purin-9-yl]cyclopentanecarboxylic acid ethylamide, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-nitrophenyl)piperidin-4-yl]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-((3S)-pyrrolidin-3-ylamino)-purin-9-yl]cyclopentane-1,2-diol dihydrochloride, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-nitrophenyl)pyrrolidin-3-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(R)-ylamino]-purin -9-yl]cyclopentane-1,2-diol,(1S,2R,3R,5R)-3-hydroxymethyl-5-[6-((3R)-pyrrolidin-3-ylamino)-purin-9-yl]cyclopentane-1,2-diol,(1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, 4(R)-1-benzyl-4-[9-(2,3-dihydroxy-4-hydroxymethylcyclopentyl)-9H-purin-6-ylamino]pyrrolidin-2-one hydrochloride, (1R,2S ,3R,5S)-5-methyl-3-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-bromopyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol,(1R,2S,3R,5R)-5-[6-[1-(5-chloropyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol,(1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(pyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, 4(S)-1-benzyl-4-[9-(2,3-dihydroxy-4-hydroxymethylcyclopentyl)-9H-purin-6-ylamino]pyrrolidin-2-one hydrochloride, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(quinolin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-S-(4-nitrophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(4,5-bistrifluorpyridin-2 yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(5-trifluoromethylpyridin2-yl)pyrrolidin-3(S)-ylamino]-purin -9-yl]cyclopentane-1,2-diol , (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(phenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, 4-[3(S)-[9-(2,3-dihydroxy-4-hydroxymethylcyclopentyl)-9H-purin -6-ylamino]pyrrolidin-1-yl]benzonitrile, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(isoquinolin-1-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-bromoquinolin -2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(4-chlorophenyl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-[6-[1-(3-chloro-5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S ,3R,5R)-3-isopropoxymethyl-5-[6-[1-(5-trifluoromethylpyridin2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3isopropoxymethyl-5-[6-[1-(4-trifluoromethylpyridin2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyridazin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(6-methoxypyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyridazin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(-[6-[1-(4-trifluoromethylphenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-bromopyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-chlorpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(4-trifluoromethylphenyl)pyrrolidin -3(S)-ylamino2-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(-[6-[1-(4-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(3-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(3-chlorophenyl)-pyrrolidin -3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-phenylpyrrolidin-3-(S)-ylamino]-purin-9-yl]cyclopentan-1,2-diol, (1R,2S,3R,5R)-3-[6-(1-benzyl-pyrrolidin-3(S)-ylamino)purin-9-yl]5-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-[6-(1-benzyl-pyrrolidin-3(S)-ylamino)purin-9-yl]5-methoxymethylcyclopentane-1,2-diol, 5xe2x80x2-N-[1(S)-methylpropyl]-N6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3-(S)-ylcarbocyclic adenosine-5xe2x80x2-uronamide, and 5xe2x80x2-N-[1(R)-methylpropyl]-N6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3-(S)-yl]carbocyclic adenosine-5xe2x80x2-uronamide.
A preferred class of compounds of the invention is described by Formula I wherein K is N, T is hydroxymethyl or methoxymethyl, A and B are hydroxy, X is 
and n+p is 3 or 4, or pharmaceutically acceptable salts thereof. Representative compounds of this preferred class of compounds include (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(5-chloropyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-tetrahydrofuran-3,4-diol, (2R,3S,4R,5R)-2-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3(R)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(4-trifluoromethylpyridin -2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R) 2-hydroxymethyl-5-[6-[1-(5-bromopyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]- tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-(6-(1-(4-nitrophenyl)-pyrrolidin-3(S)-ylamino)-purin-9-yl) tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-(5""trifluoromethyl-3,4,5,6-tetrahydro -2H-[1,2xe2x80x2]-bipyridinyl-3-3-yl)-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-(phenylpyrrolidin-3(S)-ylamino)-purin-9-yl]tetrahydrofuran-3,4-diol , (2R,3R,4S,5R)-2-hydroxymethyl -5-[6-(1-pyridin-2-ylpyrrolidin-3(S)-ylamino]-purin-9-yl ]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(4-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[f-(5-methylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(5-thiophen-2-ylpyridin-2-yl)-pyrrolidin -3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5- [6-[1-(5-methylmercaptopyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(6-methoxypyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(6chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]- tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(6-chloropyridazin-3-yl)pyrrolidin-3-ylamino]-purin-9-yl]-tetrahydrofuran-3,4-diol. (2R,3R,4S,5R)-2-methoxymethyl-5- [6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-nitrophenyl)piperidin-4-yl]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-((3S)-pyrrolidin-3-ylamino)-purin -9-yl]cyclopentane-1,2-diol dihydrochloride, (1S,2R,3R,5R)-3-hydroxymethyl-5- [6-[1-(4-nitrophenyl)pyrrolidin-3-,ylamino]-purin-9-yl]cyclopentane-1 ,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(R)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-((3R)-pyrrolidin-3-ylamino)-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin -9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-bromopyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-chloropyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(i-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(pyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(quinolin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-S-(4-nitrophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(4,5-bistrifluorpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(5-trifluoromethylpyridin2-yl)pyrrolidin-3(S)-ylamino]-purin -9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(phenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, 4-[3(S)-[9-(2,3-dihydroxy-4-hydroxymethylcyclopentyl)-9H-purin-6-ylamino]pyrrolidin-1-yl]benzonitrile, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6- [1-(isoquinolin-1-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-bromoquinolin -2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(4-chlorophenyl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-[6-[1-(3-chloro-5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5- [6- [1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyridazin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(6-methoxypyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyridazin3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(-6-[1-(4-trifluoromethylphenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-bromopyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-chlorpyridin-2-yl)pyrrolidin-31S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-4-trifluoromethylphenyl)pyrrolidin-3(S)-ylamino1-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(-[6-[1-(4-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(3-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(3-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-phenylpyrrolidin-3-(S)-ylamino]-purin-9-yl]cyclopentan-1,2-diol, (1R,2S,3R,5R)-3-[6-(1-benzyl-pyrrolidin-3(S)-ylamino)purin-9-yl]5-hydroxymethylcyclopentane-1,2-diol, and (1R,2S,3R,5R)-3-[6-(1-benzyl-pyrrolidin-3(S)-ylamino)purin-9-yl]5-methoxymethylcyclopentane-1,2-diol.
Another preferred class of compounds of the invention is described by Formula I wherein Q is CH2,K is N, T is 
wherein R1 is H and R2 is lower alkyl, A and B are hydroxy, X is 
and n+p is 3 or 4, or pharmaceutically acceptable salts thereof. Representative compounds of this other preferred class of compounds include , (1S,2R,3S,4R)-2,3-dihydroxy-4-[6-[1-(5-trifluormethylpyridin-2-yl)pyrrolidin-3-ylamino]-purin-9-yl]cyclopentanecarboxylic acid ethylamide, 5xe2x80x2-N-[1 (S)-methylpropyl]-N6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3-(S)-yl]carbocyclic adenosine -5xe2x80x2-uronamide, and 5xe2x80x2-N-[1(R)-methylpropyl]-N6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3-(S)-yl]carbocyclic adenosine-5xe2x80x2-uronamide.
A more preferred class of compounds of the invention is described by Formula I wherein Q is CH2, K is N, T is hydroxymethyl or methoxymethyl, A and B are hydroxy, X is 
and n+p is 3 or 4, or pharmaceutically acceptable salts thereof. Representative compounds of this more preferred class of compounds include (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-nitrophenyl)piperidin -4-yl]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-((3S)-pyrrolidin-3-ylamino)-purin-9-yl]cyclopentane-1,2-dihydrochloride, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-nitrophenyl)pyrrolidin-3-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(R)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-((3R)-pyrrolidin-3-ylamino)-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-bromopyridin -2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-chloropyridin-2-yl]pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[l-(4-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(pyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(quinolin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-S-(4-nitrophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(4,5-bistrifluorpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(5-trifluoromethylpyridin2-yl)pyrrolidin-3(S)-ylamino]-purin -9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(phenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, 4-[3(S)-[9-(2,3-dihydroxy-4-hydroxymethylcyclopentyl)-9H-purin-6-ylamino]pyrrolidin-1-yl]benzonitrile, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(isoquinolin-1-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-bromoquinolin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(4-chlorophenyl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-[6-[1-(3-chloro-5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyridazin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(6-methoxypyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyridazin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(-[6-[1-(4-trifluoromethylphenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-bromopyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-chlorpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(4-trifluoromethylphenyl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(-6-[1-(4-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(3-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(3-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-phenylpyrrolidin-3-(S)-ylamino]-purin-9-yl]cyclopentan-1,2-diol, (1R,2S,3R,5R)-3-[6-(1-benzyl-pyrrolidin-3(S)-ylamino1purin-9-yl]5-hydroxymethylcyclopentane-1,2-diol, and (1R,2S,3R,5R)-3-[6-(1-benzyl-pyrrolidin-3(S)-ylamino)purin-9-yl]5-methoxymethylcyclopentane-1,2-diol.
Most preferred compound of the present invention include (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol and (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(4trifluoromethylpryridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane1,2-diol.
Compounds of this invention may be prepared by known methods or in accordance with the reaction sequences described below. The starting materials used in the preparation of compounds of the invention are known or commercially available, or can be prepared by known methods or by specific reaction schemes described herein.
Compounds of Formula I, wherein K is N, Q is O and T is R3Oxe2x80x94CH2, may be prepared by reacting commercially-available 6-chloropurine riboside with various unsubstituted, alkyl, aralkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl azacycloalkylamines or protected derivatives thereof (hereinafter, xe2x80x9cappropriate starting aminesxe2x80x9d) as exemplified below.
Compounds of Formula I, wherein K is N, Q is O and T is R1R2Nxe2x80x94Cxe2x95x90O are similarly prepared starting with the product of Reaction Scheme A. In this reaction, 6-chloropurine riboside, with the 2xe2x80x2-and 3xe2x80x2-hydroxyl groups of the ribose ring protected, is treated with an oxidant, for example a Jones reagent, and the product acid treated with either dicyclohexlcarbodiimide (DCC) or BOP-Cl in the presence of a selected amine, to yield the 5xe2x80x2-alkylcarboxamide derivative. 
Suitable starting materials for compounds of Formula I wherein K is N, Q is CH2 and T is R1R2Nxe2x80x94Cxe2x95x900, may be prepared as described by Chen et al., Tetrahedron Letters 30: 5543-46 (1989). Alternatively, Reaction Scheme B may be used to prepare such starting materials. In carrying out Reaction Scheme B, the 4-ethylcarboxamide derivative of 2,3-dihydroxycyclopentylamine, prepared as described by Chen et al., is reacted with 3-amino-2,4-dichloropyrimidine. The product of this initial reaction is then heated with an aldehydylamidine acetate, for example formamidine acetate in dioxane and methoxyethanol, for a time sufficient to effect ring closure (from about 30 min to about 4 hours), thereby yielding a product which may be conveniently reacted with appropriate starting amines in the manner described below, to give the compounds of the invention. The order of reaction is not critical. For example, the intermediate formed in Reaction Scheme B could be reacted with an appropriate starting amine, followed by ring closure to yield the desired final product. 
Various amines, useful in forming the compounds of this invention, may be prepared by methods known in the art, or by methods described herein.
Diastereomeric mixtures of compounds or intermediates useful in preparing compounds of the present may be separated; into single racemic or optically active enantiomers by methods known in the art; for example. by chromatography, fractional distillation or fractional crystallization of d- or l-(tartarate, dibenzoyltartarate, mandelate or camphorsulfonate) salts.
The N6-substituted adenosines and carbocyclic adenosines of the invention may be formed by reacting 6-chloropurine riboside or the products of Reaction Schemes A or B with various appropriate starting amines, as exemplified in Reaction Scheme C. 
Where Xxe2x80x2 and Yxe2x80x2 are X and Y as defined hereinabove, or protected derivatives thereof.
The N6-substituted-Nxe2x80x2alkyl-deazaaristeromycins of the invention may be prepared as shown in Reaction Scheme D. 
Compounds of the present invention which may act as pro-drugs include those compounds wherein the hydroxyl groups on the ribose or cyclopentane ring are substituted with groups Rxe2x80x2 and Rxe2x80x3 as defined above for Formula I. These may be prepared by known methods and are exemplified by the preparations shown in Reaction Scheme E, below. 
Treatment of the dihydroxy compounds with a chloroformate ester in the presence of an organic base, for example triethylamine, will give the corresponding bis-carbonate. The alkoxymethylene acetal may be prepared by treatment with the corresponding orthoester in the presence of a catalytic amount of p-toluenesulfonic acid. The carbonate is available by treatment with 1,1xe2x80x2-carbonyldiimidazole and the thiocarbonate by treatment with thiocarbonyldiimidizole. The alkyl and dialkylcarbamoyl derivatives may be prepared by treatment with the corresponding alkyl isocyanate or dialkyl carbamoyl chloride in the presence of an organic base respectively.
Compounds of the present invention wherein K is Nxe2x86x92O, i.e., the N-oxides, may be prepared by oxidation of the corresponding adenosine or carbocyclic adenosine by known methods, for example by treatment with hydrogen peroxide in acetic acid.
The 2xe2x80x2-O-alkyl derivatives may be prepared by known methods, for example by reaction of the appropriate starting amine with 6-chloro-9-(2xe2x80x2-O-methyl-b-D-ribofuranosyl)-9H-purine.
Functional groups of starting compounds and intermediates that are used to prepare the compounds of the invention may be protected by common protecting groups known in the art. Conventional protecting groups for amino and hydroxyl functional groups are described, for example, in T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley, New York (1984).
Hydroxyl groups may be protected as esters, such as acyl derivatives, or in the form of ethers. Hydroxyl groups on adjacent carbon atoms may advantageously be protected in the form of ketals or acetals. In practice, the adjacent 2xe2x80x2 and 3xe2x80x2 hydroxyl groups of the starting compounds in Reaction Schemes A and B are conveniently protected by forming the 2xe2x80x2,3xe2x80x2 isopropylidene derivatives. The free hydroxyls may be restored by acid hydrolysis, for example, or other solvolysis or hydrogenolysis if reactions commonly used in organic chemistry.
Following synthesis, compounds of the invention are typically purified by medium pressure liquid chromatography (MPLC), on a chromatotron, radially accelerated thin layer chromatography, flash chromatography or column chromatography through a silica gel or Florisil matrix, followed by crystallization. For compounds of Formula I wherein K is N, Q is O and T is R3Oxe2x80x94CH2, typical solvent systems include chloroform:methanol, ethyl acetate:hexane, and methylene chloride:methanol. Eluates may be crystallized from methanol, ethanol, ethyl acetate, hexane or chloroform, etc.
For compounds of Formula I, wherein K is N, Q is O, and T is R1R2Nxe2x80x94Cxe2x95x90O, typical solvent systems include chloroform:methanol. For example, eluates may be crystallized from 50-100% ethanol (aqueous).
For compounds of Formula I, wherein Q is CH2, K is N or CH, and T is R1R2Nxe2x80x94Cxe2x95x90O, typical solvent systems include methylene chloride:methanol. For example, eluates may be crystallized from ethyl acetate with or without methanol, ethanol or hexane.
Compounds requiring neutralization may be neutralized with a mild base such as sodium bicarbonate, followed by washing with methylene chloride and brine. Products which are purified as oils are sometimes triturated with hexane/ethanol prior to final crystallization.
The method of the present invention is further illustrated and explained by the following Examples.